## Proposed Registration of the New Active Ingredient Cyantraniliprole

An Insecticide for Use on Multiple Commodities, Ornamentals, Turfgrass, and in

Commercial or Residential Buildings

Approved by:

# ~th**~**

Date: Lois Rossi, Director Registration Division

Office of Pesticide Programs2 

### Proposed Registration of the New Active Ingredient Cyantraniliprole

Regulatory Rationale

The Agency is proposing to grant an unconditional registration under section 3(c)(5) of the Federal Insecticide, Fungicide, and Rodentic ide Act (FIFRA)of the new active ingredient cyantraniliprole formulated as a technical product and f ourteen end-use products. The proposed ne w uses for this insecticide are: Agricultural crops bushberry (subgroup 13-07B); fruit, citrus (group 10-10); fruit, pome (group 11-10); fruit, stone (group 12-12); nut, tree (group 14-12); oilseed (group 20); vegetable, Brassica leafy (group 5); vegetable, bulb (group 3-07); vegetable, cucurbit (group 9); vegetable, fruiting (group 8-10); vegetable, leafy (excep t Brassica) (group 4) vegetable, tuberous and corm (subgroup 1C)

Ornamentals and turf ornamental plants, shrubs, trees in and around greenhouses, nurseries, lath- and shade-houses, and interior plantscapes landscape and recreational turfgr ass (including golf courses)

sod farms Structures and equipment in and around agricultu ral, commercial, and residential structures (excluding food/feed handling establishments) transportation equipment

Product formulations include liquid, granular, and bait. Methods of application for liquid applications include aerial and ground broadcast; so il application; chemigation; and seed treatment. Maximum single application rates are 0.42 lb. a.i./A for liquid or granular applications; 0.69 lb. a.i./A for seed treatments. The maximum annual application rate is 0.42 lb. a.i./A/year for liquid or granular ap plications.

I. Chemical Information

Chemical Name: cyantraniliprole, 3-bromo-1-(3-chloro-2-pyridinyl)- N -[4-cyano-2-methyl-6- [(methylamino)carbonyl]phenyl]-1 H -pyrazole-5-carboxamide

EPA PC Code: 090098

Chemical Abstracts Servi ce (CAS) Number: 736994-63-1

IRAC MoA Classification: Group 28 - Ryanodine receptor modulators

Mode of Action: unregulated activat ion of insect RyR channels leading to internal calcium store depletion and impaired regulation of muscle contra ction, causing paralysis and eventual death3 Registrants: E.I. du Pont de Nem ours & Company and Syngenta Crop Protection

Proposed Products:

File Symbol product name formulation use sites (with crop group #)

352-ILA Cyantraniliprole

Technical 96.7%

technical - Agricultural crops bushberry (subgroup 13-07B); fruit, citrus (group 10-10); fruit, pome (group 11-10); fruit, stone (group 12-12); nut, tree (group 14-12); oilseed (group 20); vegetable, Brassica leafy (group 5); vegetable, bulb (group 3-07); vegetable, cucurbit (group 9); vegetable, fruiting (group 8-10); vegetable, leafy (except Brassica), (group 4) vegetable, tuberous and corm (subgroup 1C) - industrial, public, & residential: turf,

ornamentals - commercial production: ornamentals, sod

farms - in & around residential, public, commercial, agricultural structures; transportation vehicles: indoors - spot or crack & crevice only outdoors - spot; crack & crevice; band - in & around residential, commercial, agricultural structures: scatterbait and bait

stations

352-ILT Benevia 10.26% OD

0.83 lb ai/gal - nut, tree 14-12 - oilseed 20 (inc ludes cotton) - vegetable, bulb 3-07 - vegetable, tuberous & corm 1C

352-ILO Exirel 10.20% SE

0.83 lb ai/gal - bushberry 13-07B - fruit, citrus 10-10 - fruit, pome 11-10 - fruit, stone 12-12 - nut, tree 14-12 - vegetable Brassica leafy 5 - vegetable, bulb 3-07 - vegetable, cucurbit 9 - vegetable, fruiting 8-10 including eggplant, pepper, tomato in commercial greenhouses - vegetable, leafy except Brassica 44 352-IAN Verimark 18.66% SC

1.67 lb ai/gal - fruit, citrus 10-10 - vegetable Brassica leafy 5 - vegetable, cucurbit 9 - vegetable, fruiting 8-10 - vegetable, leafy except Brassica 4 - vegetable, tuberous & corm 1C

352-ILI Dermacor Z-103

seed treatment 50% FS

5.21 lb ai/gal - rapeseed (canola)

- mustard seed

352-IAE Fly Control Bait 0.5% RB - in & around residential, commercial, agricultural structures: scatterbait and bait

stations

352-IAI SC Insect Control 18.66% SC

1.67 lb ai/gal - in & around residential, public, commercial, agricultural structures; transportation vehicles: indoors - spot or crack & crevice only' outdoors - spot; crack & crevice; band

352-IAL T&O Insect

Control 18.66% SC

1.67 lb ai/gal - outdoor turfgrass & ornamentals (residential & public incl. golf courses) - interior plantscapes

- sod farms

352-IAG GH&N Insect

Control 18.66% SC

1.67 lb ai/gal - ornamentals and "grassy, weedy, mulched, or bare soil areas" in & around greenhouses, nurseries, shadehouses, lathhouses - ornamentals in interior plantscapes

100-

RUER A169101B CP 20% + 20%

WG vegetable Brassica leafy 5 vegetable, cucurbit 9 vegetable, fruiting 8-10 vegetable, leafy except Brassica 4 vegetable, tuberous & corm 1C

100-

RUEE Mainspring 20% + 20%

WG - ornamentals in commercial greenhouse &

nurseries - certain crops in commercial greenhouse &

nurseries: .vegetable, Brassica leafy 5 .vegetable, cucurbit 9 .vegetable, fruiting 8-10

100-

RUEG A16901B

Residential 20% + 20%

WG - outdoor residential ornamentals

100-

RUEU A16901B Turf 20% + 20%

WG - turfgrass (residential & public including golf courses)

- sod farms5 100-

RUEN A17960A ST

seed treatment 48.8% FS 600 g/l - potato
- sunflower

100-RURI A17960B ST

seed treatment 48.8% FS 600 g/l - potato
- sunflower

II. Human Health Risk

A summary of the human health eff ects and risk of cyantraniliprole as assessed in the Agency document entitled “Cyantraniliprole. Aggregate Human Health Risk Assessment for the Proposed New Uses of the New Active Insecticide, including Ag ricultural Uses on Brassica (Cole) Leafy Vegetables (Group 5), Bulb Vegetables (Group 3-07), Bushberries (Group 13-07B ), Citrus Fruit (Group 10-10), Cotton, Cucurbit Vegetables (Group 9), Fruiting Vegetables (Group 8-10), Leafy Vegetables ( non-Brassica) (Group 4), Oilseeds (Group 20), Pome Fruits (Group 11-10), Stone Fruits (Group 12), Tree Nuts (Group 14), Tuberous and Corm Vegetables (Subgroup 1C); Seed Treatm ent Uses on Canola (Rapeseed), Mustard Seed, Sunflowers, and Potatoes; and Residential, Commercial , and Agricultural Uses on Ornamentals, Turfgrass (including Sod Farms and Golf Courses), and Struct ural Buildings (including Indoor Crack/Crevice and Outdoor Broadcast)" is provided below.

A. Summary of Toxicological Effects

Cyantraniliprole is a second-generation ryanodine recep tor (RyR) insecticide belonging to the diamide class of chemistry whose pesticidal mode of action (MOA) is through unregulated activation of insect RyR

channels. This leads to internal calcium store de pletion and impaired regulati on of muscle contraction, causing paralysis and eventual death of the insect. Mammalian RyR are shown to be 350 to >2500 times less

sensitive than those of insects. In general, cyantraniliprole admi nistration in mammals produces both adverse and adaptive change s in the liver, thyroid gland, and adre nal cortex. With repeated dosing, consistent findings of mild to moderate increases in liver weights across multiple species (rats, mice, dogs) are observed. Dogs appear to be more sensitive than rats and mice; cyantranilip role produces adverse liver effects (increases in alkalin e phosphatase, decreases in cholesterol, and decreases in albumin) in dogs at

lower dose levels than in rats. In addition, the liver effects in the dog show progressive severity with increased duration of exposure. The av ailable data also show thyroid hormone homeostasi s is altered in rats following exposure to cyantranilipro le after 28 or 90 days due to e nhanced metabolism of the thyroid hormones by the liver. However, cyantraniliprole is not a direct thyroid toxican t. Cyantraniliprole is classified as “Not Likely to be Carcinogenic to Humans” based on the ab sence of increased tumor incidence in acceptable/guideline carcinogenicity studies in rats and mice. In addition, there are no genotoxicity, mutagenicity, neurotoxicity, or imm unotoxicity concerns. There are also no developmental or reproductive toxicity concerns. There is no evidence of an adverse effect attributable to a single dose.

B. Food Quality Protection Act Safety Factor (FQPA SF)

EPA has determined that reliable data show the safety of infants and children woul d be adequately protected if the Food Quality Protection Act Safety Factor (FQP A SF) for cyantraniliprole were reduced to 1x. That decision is based on the following findings:

• The toxicity database for cyantraniliprole is complete.6 • There are no indications in any of the available studies that the nervous system is a target for cyantraniliprole. Effects indica tive of neurotoxicity are not seen in the neurotoxicity screening battery at or above the limit dose levels in acute (2,000 mg/kg) and 90-day (1,000 mg/kg) neurotoxicity studies.

• There is no evidence of susceptibi lity in developmental toxicity studies in rats and rabbits. The developmental toxicity study in ra ts is tested up to the limit dos e (1,000 mg/kg/day). In the rabbit developmental toxicity study decrease in fetal body weight is seen at a dose higher than that resulting in maternal effects. In the reproductive toxici ty study, increased incidenc e of thyroid follicular epithelium hypertrophy/hyperpla sia occurs in fetal 1 (F 1 ) parental animals at a dose lower than that for the parental (P) generation. A clear No -Observed Adverse Effect Level (NOAEL) (1.4 mg/kg/day) is established for F 1 parental animals, and the Point of Departures (PODs) selected for risk assessment from the dog studies (1 or 3 mg/kg/da y) are protective of the effect (thyroid effect)

seen in the F 1 parental animals. In addition the submitte d data support the conclusion that the effects on the thyroid are secondary to effects on the liver.

• The exposure databases are complete or are estim ated based on data that reasonably account for potential exposures. The chronic dietary food exposure assessment was conservatively based on 100% crop treated (CT) assumptions, average residue levels from field trials, and conservative ground and surface drinking water m odeling estimates. New 2012 Residential Standard Operating Procedures (SOPs) are used to assess post-applica tion exposure to children including incidental oral exposure. The residential post-a pplication assessment assumes that maximum application rates are applied and that hand-to-mouth ac tivities occur on the day of a pplication. All of the exposure estimates are based on conservative, health-p rotective assumptions and are not likely to

underestimate risk.

C. Toxicological End Points and Doses Us ed in the Human Heal th Risk Assessment

1. Acute: No acute dietary toxicity endpoint was selected as an effect becaus e no effect attributed to a single

dose was identified in the ma mmalian toxicology database.

2. Chronic Dietary (all populations): EPA established a chronic re ference dose (cRfD) and a Chronic Population Adjusted Dose (cPAD) for cyantranilipr ole of 0.01 mg/kg body wt/da y, based on the NOAEL of 1 mg/kg body wt/day from a 1-year oral study in dogs and an FQPA Safety F actor of 1. In this study, effects indicative of liver toxicity (increased liver wei ghts and alkaline phosphatase activity), and significant

decreases in albumin level were observed at the Lo west Observed Adverse Effect Level (LOAEL) of 6 mg/kg body wt/day.

3. Short- and Intermediate-Term Oral: EPA selected the NOAEL of 3 mg/kg body wt/day from the 90- day oral study in dogs, based on effects observed in th e co-critical 28-day and 90- day toxicity studies in dogs. In the 90-day study, a coll ection of treatment-related effects indicative of liver toxicity were observed at the LOAEL = 32 mg/kg body wt/day. The eff ects included decreases in total protein, albumin, and cholesterol in males and females; increases in alka line phosphatase in males and females; increases in alanine aminotransferase in females; and increases in liver weights in males and females. In the co-critical 28-day study, decreases in body weight, food consump tion, food efficiency, and changes in clinical chemistry (increased ALP, decreased cholesterol, and decreased albumin) were observed at the LOAEL = 35 mg/kg body wt/day (lowest dose tested). The level of concern for assessing short- and intermediate-term occupational exposure to cyantran iliprole is a margin of expos ure (MOE) that is less than 100.7 4. Short-Term Dermal: No short-term dermal toxicity endpoint was selected because systemic toxicity was not seen in 28-day dermal toxicity in rats at the limit dose (1,000 mg/kg/day). There are no concerns for developmental or reproductive toxicity or neurotoxicity.

5. Short-Term Inhalation: EPA selected the NOAEL of 0.1 mg/L from the 28-day inhalation study in rats.

A LOAEL was not established because the highest concentration tested (0.1 mg/L) did not demonstrate any

adverse effects.

6. Cancer: EPA has classified cyantraniliprole as “Not likely to be Carcinogenic to Humans” based on data showing lack of treatment-related increase in tumor inci dence in the rat and mouse carcinogenicity studies. Mutagenic concern was not reported in the mutagenicity studies.

D. Cumulative Effects

Unlike other pesticides for which EPA has followe d a cumulative risk approach based on a common mechanism of toxicity, EPA has not found cyantranilipro le to share a common mech anism of toxicity with any other substances, and cyantrani liprole does not appear to produce a toxic metabolite produced by other substances. For the purposes of this action, therefore, EPA has assumed that cyantraniliprole does not have a common mechanism of toxicity with other substances.

E. Aggregate Risk Assessment

1. Acute Dietary Risk An acute aggregate risk assessment ta kes into account acute exposure estimates from dietary consumption of food and drinking water. No adverse effect resu lting from a single oral exposure was identified and therefore no acute dietary e ndpoint was selected. Cyantraniliprole is not expected to pose an acute risk.

2. Chronic dietary risk EPA has concluded that chronic exposure to cyantran iliprole from food and water will utilize 50% of the cPAD for children 1-2 years old (the population group receiving the grea test exposure) and 22% of the general U.S. population.

3. Short-term risk Short-term aggregate exposure takes into account short- term residential exposure plus chronic exposure to food and water (considered to be a background exposure leve l). Cyantraniliprole is proposed for uses that

could result in short-term residentia l exposure, and the Agency has determined that it is appropriate to aggregate chronic exposure through food a nd water with short-term residentia l exposures to cyantraniliprole. Residential exposure estimates of a ll possible scenarios are not of conc ern. Short-term inhalation MOEs range from 22,000 to 220,000,000. Furthermore, these calc ulated risk estimates are highly conservative because the inhalation exposure POD is based on an exposure duration of 24 hours per day.

Using the exposure assumptions desc ribed in this unit for short-term exposures, EPA has concluded the combined short-term food, water, and residential expos ures result in aggregate MO Es of 290 for children 1-2 years old (the population group receiving the greatest exposure) and 22,000 for adults. Because EPA’s level of concern for cyantraniliprole is a MOE of 100 or below, these MOEs are not of concern.

4. Intermediate-term risk Intermediate-term aggregate exposure takes into account intermediate-term residential exposure plus chronic exposure to food and water (considered to be a backgr ound exposure level). For adults, intermediate-term exposure is not expected for the resi dential exposure pathway. The intermediate-term aggregate risk would8 be equivalent to the chronic dietar y exposure estimate. For children 1 to <2 years old, the short-term aggregate risk is protective of the intermediate-term duration.

5. Aggregate cancer risk for U.S. population

Based on the lack of evidence of carcinogenicity in two adequate rodent carcinogenicity studies, cyantraniliprole is not expected to pose a cancer risk to humans.

F. Occupational Risk Assessment

1. Handler Exposure and Risk

Occupational handler and post-appli cation exposure may occur by the de rmal and inhalation routes of exposure only. Since there is no dermal hazard from cyantraniliprole, only inhalation exposures were quantitatively assessed. Also, since no acute toxicity effects were found fo r cyantraniliprole, only short- and

intermediate-term inhalation risk estimates were calculated.

a. Agricultural Field Uses

The results of the occupational handler exposure and ri sk assessment indicate that short- and intermediateterm inhalation risks do not exceed EPA’s Level of Concern (LOC) (i.e. an MOE < 30 for short-term exposures and an MOE < 100 for intermediate-term expos ures) at baseline mitigation (no PPE). Since the short- and intermediate-term PODs are the same, th e inhalation MOEs are al so the same, ranging from 1,200 to 3,900,000.

EPA has no data to assess exposures to pilots using open cockpits. The only data available is for exposure to pilots in enclosed cockpits. Theref ore, risks to pilots are assessed us ing the engineering control (enclosed cockpits) and baseline attire (long-s leeve shirt, long pants, shoes, a nd socks); per the Agency’s Worker Protection Standard stipulations for engineering controls, pilots are not required to wear protective gloves for the duration of the application. There are no risk estimates of concern for aerial applicators.

b. Agricultural Seed Treatment Uses

Based on the anticipated use patter ns and current labeling, types of equipment and techniques that can potentially be used, some occupation al handler exposure is expected from the proposed seed treatment uses. The quantitative exposure/risk assess ment developed for occupational ha ndlers is based on the following

scenarios: Mixing/loading liquids for pot ato seed piece treatment, Planting potato seed pieces, Mixing/loading liquids for commer cial seed treatment, and Planting treated seed.

The results of the occupational handler exposure and risk assessment indicate that short-term inhalation risk estimates do not exceed EPA's LOC (i.e. an MOE < 30 for short-term exposures) at baseline, without mitigation from PPE. Short-term exposure risk estimates are protective of intermediate-term exposure risk estimates because the throughput (amount of seed treated) is greater th an, or equal to, the throughput of intermediate-term exposure. The calculated inha lation risk estimates do not exceed EPA's LOC for intermediate-term exposures (i.e. an MOE < 100) at ba seline, without mitigation from PPE. The inhalation MOEs range from 370 to 4,000 for primary handlers (treaters) and 2,200 to 190,000 for secondary handlers (planters).9 2. Occupational Postapplic ation Exposure and Risk

An occupational post-application exposure and risk assessment was not conducted because a dermal hazard was not identified for cyantraniliprole.

III. Environmental Risk

A summary of the environmental fate and ecological effect s and risks of cyantraniliprole as assessed in the Agency document entitled “Environmental Risk Assessment of Proposed New Global Chemical Cyantraniliprole on Bushberries, Citr us, Cotton, Oil Seeds, Pome Fruit, Stone Fruit, Tree Nuts, Vegetables (Bulb, Corm and Tuberous, Cucurbit , Fruiting, Leafy Brassica, and L eafy-Non-Brassica), and Professional Products (Fly Bait, Indoor and Outdoor Insect Control for Public Health Pests Such as Cockroaches, Ants, Flies, Termites, Nuisance Insect Pests, Turfgr ass and Ornamentals, Tree Injection, and Production Greenhouse and Nursery Ornament als)" is provided below.

A. Environmental Fate

Cyantraniliprole is a systemic insectic ide. It is soluble at neutral pH and given its low vapor pressure (3.85 x 10-17 mm Hg) and Henry’s Law constants (1.70 x 10- 18 atm*m 3 /mol), is not consider ed volatile and is not likely prone to atmospheric transport. While cyantran iliprole is subject to both abiotic alkaline hydrolysis (t1⁄2 = 21 hrs) and photodegradation in aqueous (t1⁄2= 8 hrs) and moist soil environmen ts and biotic (aerobic

and anaerobic biotransformation in te rrestrial and aquatic environments, t1⁄2 range from 2 days to 3 months) degradation, the chemical degrades into a total of 13 degrad ation products. Of these degradates, eight are major and five are minor. Based on degradate aerobic soil metabolism and mobility studies, six of the eight major degradates had longer dissipation half-life (DT 50 ) values (more persistent) and three of the eight degradates were more mobile than the parent cyantraniliprole. A ccording to the Food and Agriculture Organization (FAO) classification system, based on orga nic carbon partitioning coeffi cients, cyantraniliprole is characterized as moderately mob ile. Bioconcentration factor data ( BCF value <1 in whole fish) indicate that cyantraniliprole is not likely to bioaccumulate.

Given the uncertainty of the behavior and toxicity of these degradates, their toxicity is assumed to be equivalent to the parent compound, cyantraniliprole. Fo r the aquatic exposure mode ling, a total toxic residue approach (considers the parent compound and eight major degradates including two degradates from terrestrial field studies) was utilized. For surface water, peak estimated environmental concentrations (EECs) ranged from 0.23 μg/L from cyantraniliprole use on trees using the Oregon Christmas tree scenario to 38 μg/L from cyantraniliprole use on cotton using the North Carolina cotton scenario. For pore water, peak EECs ranged from 0.22 μg/L from cyantraniliprole use on trees using the Oregon Christmas tree scenario to 37 μg/L from cyantraniliprole use on ra peseed using the North Dakot a wheat scenario.

B. Ecological Risk

Ecological risk characterizat ion integrates the results of the exposur e and ecotoxicity data to evaluate the likelihood of adverse ecological effect s. The means of integrating the results of exposure and ecotoxicity data is called the risk quotient method. For this method, risk quotients (RQs) are calculated by dividing exposure estimates by ecotoxicity values, both acute a nd chronic (RQ = Exposure/To xicity). RQs are then compared to EPA's LOCs. The LOCs are criteria used by the Agency to indicate potential risk to non-target organisms. The criteria indicate whether a pesticide, when used as directed, has the po tential to cause

adverse effects to non -target organisms.10 In some cases, toxicity is noted as non-definitive since testing was either not high enough or not low enough and an exact value was not determined. Although an actual value can’t be note d, a bound can be put on the toxicity as information is known.

Risks to Aquatic Organisms

Fish Cyantraniliprole is classified as “sli ghtly to moderately toxic” to freshwat er fish on an acute exposure basis. A conservative calculation using the peak aquati c EEC (37.97 μg ai/L) and the typical end product LC 50 (2,400 μg ai/L) resulted in an RQ of 0.016. This is well below the acute risk to listed species LOC of 0.05. Consequently, direct acute risks to freshwater fish a nd aquatic-phase amphibians, for which fish serve as surrogates, from the proposed uses of cyantr aniliprole are not considered likely.

Risk quotients calculated for chroni c exposures to cyantran iliprole ranged from <0.001 to 0.003 and were all

well below the chronic risk to listed and non-listed species LOC of 1. Th e risk quotient analysis indicated

that direct chronic effects to freshwater fish are not expected; none of the risk quot ients exceeded the chronic

risk LOC of 1.

Risk quotients could not be calculated for direct acute e ffects to estuarine/marine fish because the toxicity value was non-definitive. In lieu of this, the most se nsitive toxicity va lue can be compared with the peak

EEC. The most sensitive LC 50 (>12,000 μg total ai/L), although non-defin itive, is much larger than the peak aquatic EEC of 37.97 μg ai/L. There wa s precipitate in this toxicity test and measured concentrations were not centrifuged or filtered; therefore, the amount of dissolved cyantranilipro le is uncertain, lending uncertainty to the study’s results. No mortality or sub-lethal effects were observed in any treatment group in the test. Furthermore, the LC 50 would need to be 16 times more sens itive (759 μg ai/L) to even reach the acute risk to listed species LOC of 0.05. Thus, the likelihood of advers e effects on estuarine/marine fish from direct acute exposure from the proposed uses of cyantraniliprole is considered low.

Risk quotients could not be calcula ted for chronic effects to estuar ine/marine fish because only nondefinitive toxicity data were available. Given that the No Observ ed Adverse Effect Concentration (NOAEC) was a less than value (NOAEC <750 μg ai/L), it is not possible to preclude the possibility of direct chronic risks to estuarine/marine fish. Growth parameters (length and weight) were affected at the lowest concentration tested. Although the absolute value of the NOAEC (750 μg total ai/L) is one order of magnitude higher than the highest 60-day aquatic EEC of 37.42 μg a i/L and risk concerns cannot be eliminated on this alone. The risks will be reduced by mitigation (see Proposed Labeling Changes, below).

Invertebrates Cyantraniliprole ranged in toxicity from slightly to very highly toxic to freshwater invertebrates on an acute exposure basis. Risk quotients for acute exposures to freshwater invertebra tes ranged from 0.011 to 1.9. Most uses exceeded the acute risk to listed species LOC of 0.05 and some exceeded the acute risk to nonlisted species LOC of 0.5.

Risk quotients for chronic exposures to freshwater invertebrates ranged from 0.035 to 5.8 with some uses exceeding the listed and non-listed sp ecies chronic risk LOC of 1.

Cyantraniliprole is moderately to hi ghly toxic to estuarine/marine invert ebrates on an acute exposure basis. Acute risk quotients for estuarin e/marine invertebrates ranged from <0.001 to 0.073 showing a slight

exceedance of the acute risk to lis ted species LOC of 0.05. Chronic risk quotients ranged from 0.001 to 0.23 (oyster) and < 0.001 to 0.12 (mysid shrimp). No scenar ios exceeded the listed and non-listed species chronic risk LOC of 1. Thus, while mortalit y (direct) of estuarine/marine inve rtebrates is possible following acute11 exposure for eight of the proposed us es, the likelihood of (dir ect) adverse effects from chronic exposure is

considered low.

Cyantraniliprole is highly toxic to benthic invertebrates on an acute exposure basis. Acute risk quotients for benthic invertebrates ranged from <0.001 to 0.051 but only one use exceeded the acute risk to listed species LOC of 0.05. Chronic risk quotients ranged from 0.022 to 3.7 with some uses exce eding the listed and nonlisted species chronic risk LOC of 1.

Aquatic Plants Toxicity data for technical-grade cyantraniliprole wa s non-definitive for aquatic vascular and non-vascular plants. Thus, risk quotients were no t calculated. Given the lines of eviden ce, it is unlikely that there will be direct adverse effects to aquatic pl ants based on exposure from the propo sed uses of cyantraniliprole.

Risks to Terrestrial Animals

Birds Cyantraniliprole is classified as ‘practically nontoxic’ to birds on an acute oral and sub-acute dietary exposure basis. Since all of the e ndpoints from the acute oral and sub- acute dietary toxici ty studies with birds are non-definitive ( i.e ., they are ‘greater than’ values), they we re not used to calculate RQs. Instead, the non-definitive toxicity values were directly compar ed to the Expected Environmental Concentrations (EECs). The most sensitive TGAI studies were selected (in two cases, there were more sensitive results for TEP studies, but these were also non-definitive and the lower toxicity value is probably an artifact of the largest dose of product that was given to the bird rather than the active ingredie nt itself). In all cases, none of the EECs were larger than the non-definitive toxicity va lues for the most sensitive avian species. No sublethal effects were observed in either the acute oral or sub-acut e dietary studies for any of the species tested.

The chronic dietary-based RQs range from <0.01 to 0.45. The likelihood of chronic a dverse effects in birds, reptiles, and terrestrial-phase amphibi ans from exposure to residues from the proposed cyantraniliprole uses is expected to be low.

Mammals Cyantraniliprole is classified as ‘practically nontoxi c’ to mammals on an acute or al exposure basis. Acute dose-based and dietary-based risk quo tients could not be calculated to ev aluate the risks to mammals because only non-definitive acute toxicity data were available. Instead, the non-definitive toxicity values were directly compared to the EECs. In all cases, none of the EECs were larger than the non-definitive toxicity values. Furthermore, no sub-lethal effects were observed in the acute oral toxicity study.

Seed and fruits/pods were the only food items wher e RQs did not exceed the lis ted and non-listed species chronic risk LOC (1); all other food it ems (short grass, tall grass, broadl eaf plants, and arthropods) exceeded. Chronic risk quotients for the proposed foliar spray, ba rk spray, and seed treatment uses ranged from 0.18 to

5.48.

Chronic risk quotients for soil injec tion, soil drench, drip irrigation, and applications to potted ornamentals were derived by estimating the concentr ation of cyantraniliprole in the le af biomass of the plant. Based on the screening-level RQ analysis , risk quotients ranged from 0.23 to 31.8. The proposed use on potted ornamentals was the only proposed use th at did not exceed the chronic risk LO C of 1. A screening level risk

assessment assumes that 100% of the animal’s di et has been treated w ith cyantraniliprole.12 Terrestrial Invertebrates Toxicity data for parasitic wasps, beetles, spiders, lacewings, predatory mites, a nd collembola indicated that cyantraniliprole is toxic to some terrestrial invertebrates at very low application rates (48-hr LR 50 = 0.00008 lb ai/A – parasitic wasp). Conversely, collembola, which are exposed to cyantr aniliprole through direct contact with the soil, were not found to be very sensitive to applications of cyantraniliprole (EC 50 > 1,200 mg ai/kg-soil. Likewise, earthworms demonstrated a low toxic effect to cyantraniliprole (EC 50 > 102.6 mg ai/kg-soil – based on TEP).

Honeybee toxicity data for cyantranilipr ole indicated that it is highly toxic on an acute oral and contact basis, but the endpoints were non-definitive and th e true toxicity classi fication is uncertain. Refined acute oral RQs for adult honeybees using maximum re ported concentrations in nectar and pollen were determined as the ratio of cyantraniliprole consumed in pollen/nectar (i.e., dose) to the acute LD 50 for cyantraniliprole-only TEP (0.116 μ g ai/bee) and ranged from 0.017 to 0.066 and ar e below the level of concern of 0.4.

The semi-field studies indicated tran sient effects on behavior, foraging activ ity and mortality, observations of brood health and colony strength (up to 28 days) s uggested no adverse effects from cyantraniliprole applications. The results of longer-t erm studies must be considered in the context of some uncertainties. Namely, the health of all colonies (controls and treatment) was in decline well before overwintering reductions in colony size should have occurred. However, of the thr ee studies that followed the hives through the overwintering period, most of the data suggest no long-term effects to honeybees that would

differentiate treated coloni es from control colonies.

Non-target Terrestrial and Semi-Aquatic Plants Based on the risk quotient analysis, the LOC for risk to listed terrestrial plants was not exceeded for monocots or dicots. There is some uncertainty re garding the analysis for monocots because seedling emergence data were available for only one monoco t. Onion was the most sensitive monocot in the vegetative vigor test, but data from this species we re found to be unacceptable in the seedling emergence study because of control performance problems. If the seedling emergence NOAEC for onion is ≤ 0.100, risk quotients would exceed the LOC for some uses. Currently, the most sensitive monocot seedling emergence NOAEC is 0.134 lb ai/A. Risk quotients could not be ca lculated for non-listed monocots and dicots because only non-definitive data were available for these endpoints. The listed species risk quotients are based on the NOAEC, which is more sensitive than the EC 25 . Thus, the risk quotients for lis ted species are expected to be protective of non-listed species as well. No direct effects are anticipated fo r terrestrial dicots ; however direct effects to listed monocots cannot be precl uded because of an absence of data.

IV. Proposed Regulatory Decision

The Agency is proposing to uncondi tionally grant the re gistration of the new active ingredient, cyantraniliprole, formulated as a technical product and fourteen end us e products, under sect ion 3(c)(5) of the Federal Insecticide, Fungicide, and R odenticide Act for the following uses:

Agricultural crops bushberry (crop subgroup 13-07B); fr uit, citrus (crop group 10-10); fruit, pome (crop group 11-10); fruit, stone (crop group 12-12); nut, tree (crop group 14-12); oilseed (cr op group 20); vegetable, Brassica leafy (crop group 5); ve getable, bulb (crop group 3-07); ve getable, cucurbit (crop group 9); vegetable, fruiting (crop group 8- 10); vegetable, leafy (except Brassica) (crop group 4); and vegetable, tuberous and corm (crop subgroup 1C).13 Ornamentals and turf ornamental plants, shrubs, trees in and around gr eenhouses, nurseries, lath- and shade-houses, and interior plantscapes; landscape and recreational turfgr ass (including golf courses); sod farms.

Structures and equipment in and around agricultural, comm ercial, and residential structur es (excluding food/feed handling establishments); and transportation equipment.

The Agency has determined that the registration of th ese uses will not cause any unreasonable adverse effect on the environment. In addition, EPA has granted cyan traniliprole reduced risk status compared to the currently registered pest icides for these uses.

On April 26, 2012, EPA published a Noti ce of Receipt in the Federal Re gister of an application for registration of cyantraniliprole and announced a public comment period of 30 days. Only two comments were received, one from the San Francisco Bay Regi onal Water Quality Control Board and the other from the California Stormwater Quality Association. The comm ents were similar, both requested that EPA:

“...carefully evaluate all cyantraniliprole product registration applications. Specifically, we request a full evaluation of the potential for cyantraniliprole products to cause adverse impacts in the water

column and/or sediments in California’s urban wate rways. We request that EPA consider all urban application locations and evaluate potential pathways to receiving wa ters under conditions consistent

with label instructions. The evaluation should include stable degr adates and the time required for the active ingredient to become non-toxic in the environment. If use of the pesticide consistent with the label instructions can result in toxicity in the r eceiving water, further rest rictions on use must be evaluated. We encourage EPA to pay special attent ion to application types – like control of insects around buildings and pre-construction termiticide app lications – that are being addressed in EPA’s pyrethroid Registration Reviews.”

EPA addressed these comments during the risk assessm ent by employing the Total Toxic Residue approach (i.e. including parent chemical and all potential degradates) in its eval uation of cyantran iliprole and its degradates in aquatic systems. The Total Toxic Resi due approach essentially extends the duration of the predicted EECs to account for the time it would take for both the parent and degradates of concern to dissipate in the environment. It a ssumes that the degradates have equiva lent fate and ecotoxicity properties as the parent which is a conservative assumption.

A. Data Requirements No additional studies required for proposed uses. The database is complete for the proposed uses.

B. Global Joint Review and Reduced Risk Status EPA conducted an extensive analysis of cyantranilipro le in collaboration with counterpart agencies in France, United Kingdom, Canada, and Australia. In this process, the agencies anal yzed data on such aspects of cyantraniliprole as its impact on human and animal h ealth, fate and behavior in the environment, and its effects on non-target organisms, i.e., on animals and plants other than the pests it is intended to control. In the course of this analysis, the agencies cons idered over 700 published and unpublished studies.

After the conclusion of the joint agency review of data, EPA conduc ted its own risk assessment of cyantraniliprole including a comprehensive analysis of the pesticide’s human hea lth risk, as well as an analysis of its environmental fate and ecological risk. The risk assessm ent considered cyantraniliprole's potential effects on animals, plants, soil, and water, and included detailed calcula tions of the pesticide’s potential effects.14 In addition, on September 20, 2011, EPA's Reduced Risk Committee approved cyantraniliprole as a "reduced risk" candidate for the proposed uses. Based on the committee's evaluation of the information provided, the mammalian toxicity and ecotoxicity risk profiles for cyantraniliprole are favorable compared to registered alternatives, which include organoph osphates, pyrethroids and abamecti n. The novel mode of action for cyantraniliprole fits in well with resistance management strategies.

As is expected with insecticides, aquatic invertebrates may be affected by cyantraniliprole. To mitigate risks to these and nontarget terrestr ial invertebrates, cyantraniliprole labels for foliar applications include a section on spray drift management, see below, which is inte nded to keep the pesticide on the treatment area.

C. Proposed Labeling Changes

1. For end use products used outdoors, EPA proposes to require the labeling include the following in

the Environmental Hazards section:

"Drift and runoff may be hazardous to aquatic organi sms in water adjacent to treated areas. This pesticide is toxic to aquatic inve rtebrates. This product is highly toxic to bees exposed to direct treatment or residues on blooming crops or weeds. Do not apply this product or allow it to drift to blooming crops or weeds if bees ar e visiting the treatment area.”

2. To address potential risks to aquatic organisms, for end use products used outdoors, EPA proposes to require the labeling include th e following in the Directions for Use:

“Do not make ground applications within 25’ or aer ial applications within 50’ of lakes, rivers, reservoirs, permanent streams, marshes, na tural ponds, estuaries or coastal areas.”

3. Review of the submitted residue data indicates th at the following rotational crop restrictions must

be added to the Directions for Use for the agricultural products:

• “Cereal grains (crop group 15) may not be planted immediately after use of cyantraniliprole. Cereal grai ns (crop group 15) must have a 30-day plant back interval (PBI). This is to be consistent with th e 30-day PBI for crop group 16 (forage, fodder, and straw of cereal grains).”

• “Legume vegetables (crop group 6) may not be planted immediately after use of cyantraniliprole. Legume vegetables (crop group 6) must have a 30-day PBI. This is to be consistent with the 30 day PBI for cr op group 7 (foliage of legume vegetables).”

• “Tuberous and corm vegetables (subgroup 1C) may not be planted immediately after use of cyantraniliprole. Subgroup 1C must have a 30 -day PBI. This is to be consistent with the 30-day PBI for crop group 2 (leaves of root and tuber vegetables).”

4. Residue data was not submitted to support use in food and feed handling sites, therefore, these

sites must be deleted from the label for pending product 352-IAI, “SC Insect Control.”